This R01 grant is aimed at better understanding the molecular mechanisms by which chronic exposure to drugs of abuse induces long-lasting changes in the brain's reward circuits that contribute to the complex behavioral abnormalities that define an addicted state. Our work focuses on the transcription factor, FosB, which is induced in the nucleus accumbens (NAc) and other key brain reward regions in response to chronic administration of virtually all drugs of abuse. FosB is unique in that it accumulates to appreciable levels only after chronic drug exposure and, because of its unusual stability, persists for weeks-months of withdrawal. FosB is thus one mechanism by which chronic drug exposure can drive long-lasting changes in gene expression that contribute to addiction. Indeed, considerable evidence supports the view that induction of FosB in NAc mediates a state of heightened reward and motivation that could contribute to aspects of the addiction process. In this competitive renewal, we will characterize the precise mechanisms through which FosB exerts these actions. Using state-of-the-art genome-wide chromatin assays, we will identify the genes in the NAc that are direct targets for FosB in the context of cocaine and opiate administration. Such genes, in turn, provide novel insight into the molecular and cellular basis of drug-induced neural and behavioral plasticity. Interestingly, when FosB binds to its target genes, it can either activate or repress them. Our hypothesis is that such activation vs. repressive actions are determined by the chromatin milieu of the affected gene. As well, despite the fact that cocaine and opiates induce FosB in the same subtype of NAc neuron, partially non-overlapping genes are regulated by FosB in response to the two drugs. Once again, our hypothesis is that this specificity is mediated by differences in other chromatin changes that cocaine and opiates induce at specific genes. In addition to exploring FosB's regulation of target genes, we will also characterize several mechanisms that are crucial in determining the amount and activity of FosB induced in the NAc. Together, these studies will identify many novel actions of drugs of abuse which can be exploited for the development of improved diagnostic tests and treatments for addiction. PUBLIC HEALTH RELEVANCE: We believe that the best way to ultimately develop improved diagnostic tests and treatments for drug addiction is through a better understanding of the basic biological mechanisms involved. This R01 grant renewal will contribute importantly to this goal by defining many novel genes and proteins, and therefore novel biochemical pathways and neural mechanisms, involved in the addiction process.